Synthesis of 7-substituted saccharins and 8-substituted oxicams, and a novel saccharin to oxicam transformation

Full text of DOI:10.1021/jo961955w

J . Org. Chem. 1997, 62, 1851-1853
1851
Sch em e 1a
Syn th esis of 7-Su bstitu ted Sa cch a r in s a n d
8-Su bstitu ted Oxica m s, a n d a Novel
Sa cch a r in to Oxica m Tr a n sfor m a tion
J ohn R. Proudfoot,* Usha R. Patel, and
Alexey B. Dyatkin
Boehringer Ingelheim Pharmaceuticals Inc., Research and
Development, 900 Ridgebury Road, P.O. Box 368,
Ridgefield, Connecticut 06877
Received October 17, 1996
The 4-hydroxy-1,2-benzothiazine 1,1-dioxide (oxicam)
ring system 1 is a common substructure of certain
pharmaceutically important antiinflammatory agents.1
It can conveniently be derived from the 1,2-benzoisothi-
azol-3(2H)-one-1,1-dioxide (saccharin) system 2 by ring
expansion,2 and when we recently required a general
access to 8-substituted oxicams we logically looked to
7-substituted saccharins3 as precursors. In particular we
were interested in the previously undescribed iodo com-
pounds which, by palladium-catalyzed cross coupling
reactions,4 should function as convenient precursors to
a variety of derivatives.
a
n-BuLi, THF, Me2NCOCl; (b) n-BuLi, MeI, 62%; (c) n-BuLi,
I2, 44%; (d) Pd(Ph3P)2Cl2, PhBu3Sn, NMP, 120 °C, 16 h, 69%; (e)
NaHMDS, DMSO/THF, methyl chloroacetate, 60 °C, 35% for 1a ,
36% for 1b.
constitutes a one-pot conversion of the unsubstituted
benzenesulfonamide 3 to the 7-substituted saccharins.
The carboxylation of o-lithiobenzenesulfonamides is a
convenient method for preparing 2-carboxybenzene-
sulfonamides that function as standard intermediates for
the synthesis of saccharins.5 Introduction of a dimethyl-
carbamoyl group rather than a carboxyl group allows this
approach to be applied to the synthesis of 7-substituted
saccharins as shown in Scheme 1. The dimethylcarbam-
oyl group in 4 is stable to ortho lithiation conditions and
is less effective than the sulfonamide as an ortho-
directing group.6 Lithiation occurs adjacent to the sul-
fonamide group, and reaction with iodomethane or iodine
gives the methyl (5a ) or iodo (5b) derivative which closes
to the 7-substituted saccharin 2a (62%) or 2b (44%) after
workup. The mass balance in general consists of intrac-
table polar material, although on occasion N-methyl-2-
(N,N-dimethylcarbamoyl)benzenesulfonamide (correspond-
ing to intermediate 4) has been isolated. The sequence
The 7-iodosaccharin 2b reacts with phenyltributyltin
under palladium catalysis4 to generate the 7-phenylsac-
charin 2c (69%). The 7-methyl and 7-iodosaccharin
derivatives 2a and 2b are transformed by the procedure
of Weeks et al.2c into the oxicams 1a (35%) and 1b (36%).
Intermediates related to 4 in Scheme 1 can also be
generated by reaction of a saccharin with dimethylamine
as shown by the conversion of N-allylsaccharin 2d 7 to the
sulfonamide 4a (85%) in Scheme 2. Lithiation and
iodination of 4a followed by cyclization generates N-allyl-
7-iodosaccharin 2e (68%) in a sequence that constitutes
a formal substitution of the saccharin at the 7-position.
N-allyl-7-iodosaccharin 2e can also be obtained (47%)
from N-allylbenzenesulfonamide 3a in a process analo-
gous to that shown in Scheme 1.
Scheme 2 also illustrates an alternative saccharin to
oxicam transformation that is based on the intramolecu-
lar Heck reaction of 1-(2′-bromobenzenesulfonyl)-2,5-
dihydropyrrole described by Grigg et al.8 Hydrolysis of
2e with potassium hydroxide in DMSO and reaction with
excess iodomethane give the 2,6-disubstituted N-allyl-
sulfonamide 6 (89%). Under palladium catalysis and via
an intramolecular Heck reaction, a 6-exo cyclization of 6
furnishes the bicyclic compound 7 as the major product
(61%). We identified as minor components of this reac-
tion the regioisomer 8 and 9, the product of a 7-endo ring
closure. The formation of 9 was not surprising since
(1) Lombardino, J . G.; Wiseman, E. H. Med. Res. Rev. 1982, 2, 127-
152.
(2) (a) Catsoulacos, P.; Camoutsis, C. J . Heterocycl. Chem. 1979, 16,
1503-1524. (b) Lombardino, J . G.; Kuhla, D. E. Adv. Heterocycl. Chem.
1982, 28, 73-125. (c) Weeks, P. D.; Vinick, F. J .; Breitenbach, R.; J ung,
S. J . Org. Chem. 1983, 48, 3601-3603.
(3) Some 7-substituted saccharins have been described, but with the
exception of a concise approach to the 7-chloro derivative the syntheses
are rather lengthy. (a) For 7-methoxysaccharin see: Haworth, R. D.;
Lapworth, A. J . Chem. Soc. 1924, 125, 1299-1307. (b) For 7-chloro-
saccharin see: Hlasta, D. J .; Court, J . J .; Desai, R. C. Tetrahedron
Lett. 1991, 32, 7179-7182. (c) For 7-nitro and 7-aminosaccharin see:
Hamour, G. H. J . Pharm. Sci. 1965, 52, 603-604. (d) For 7-methyl-
saccharin see: Milstein, D. US Patent 5034534.
(4) Milstein, D.; Stille, J . K. J . Am. Chem. Soc. 1979, 101, 4992.
(5) (a) Watanabe, H.; Gay, R. L.; Hauser, C. R. J . Org. Chem. 1968,
33, 900-903. (b) Lombardino, J . G. J . Org. Chem. 1971, 36, 1843.
(6) Brandsma, L.; Verkruijsse, H. Preparative Polar Organometallic
Chemistry 1; Springer-Verlag: Berlin, 1987; 208-209.
(7) Rice, H. L.; Pettit, G. R. J . Am. Chem. Soc. 1954, 76, 302-303.
(8) Grigg, R.; Santhakumar, V.; Sridharan, V.; Stevenson, P.;
Teasdale, A.; Thornton-Pett, M.; Worakun, T. Tetrahedron 1991, 47,
9703-9720.
S0022-3263(96)01955-X CCC: $14.00 © 1997 American Chemical Society

1852 J . Org. Chem., Vol. 62, No. 6, 1997
Notes
Sch em e 2a
expansion methodology providing a short and efficient
synthesis of these materials. In addition, a new route
to the oxicam nucleus via an intramolecular Heck reac-
tion on N-allyl-2-iodobenzenesulfonamides is described.
Exp er im en ta l Section
Melting points were determined on a Fisher-J ohns melting
point apparatus and are uncorrected. 1H NMR spectra were
recorded on a Bruker AC-270 spectrometer operating at 270
MHz. Elemental analyses were determined at Midwest Labo-
ratories, Indianapolis, IN. THF, dioxane, and DMSO anhydrous
grade solvents were purchased from Aldrich Chemical Co. and
used without further purification
7-Iod o-2-m eth yl-1,2-ben zoisoth ia zol-3(2H)-on e 1,1-Diox-
id e (2b) (2-methyl-7-iodosaccharin). To a solution of 3 (8.61 g,
50.3 mmol) in THF (100 mL) cooled below -30 °C was added
n-BuLi (2 M in cyclohexane, 53 mL) at such a rate that the
temperature remained below -30 °C. The mixture was stirred
at -30 °C to -40 °C for 45 min. Dimethylcarbamyl chloride
(5.0 mL, 54 mmol) was added all at once. The temperature rose
to 0 °C, and a precipitate formed. Further THF (200 mL) was
added to redissolve the precipitate, and the mixture was cooled
to -40 °C. n-BuLi (2 M in cyclohexane, 27 mL) was added below
-40 °C, and the mixture was stirred for 40 min. Iodine (12.7 g,
50 mmol) in THF (100 mL) was added rapidly, and the mixture
was allowed to warm to rt. The mixture was diluted with EtOAc
and washed with water (300 mL) and 3% aqueous KOH (100
mL). The combined aqueous phase was acidified (AcOH) and
extracted with EtOAc. The combined organic phase was dried,
filtered, and evaporated. The residue was warmed on a rotary
evaporator at 60 °C for 3 h to effect cyclization to the saccharin.
The solid residue was washed with methanol and collected by
filtration giving 2b (5.31 g). The supernatant was fractionated
over silica (eluent, hexane/CH2Cl2 to CH2Cl2/EtOAc gradient)
to give further 2b (1.92 g) (total yield, 7.23 g, 22.4 mmol, 44%):
mp 155-157 °C; 1H NMR (CDCl3) δ 8.18 (1H, dd, J ) 1, 8), 8.03
(1H, dd, J ) 1, 8), 7.49 (1H, apparent t, J ) 8), 3.29 (3H, s);
MS(CI) 324 MH+. Anal. Calcd for C8H6NO3SI: C, 29.74; H,
1.87; N, 4.34. Found: C, 30.05; H, 1.86; N, 4.21.
2-Met h yl-7-p h en yl-1,2-b en zoisot h ia zol-3(2H )-on e 1,1-
Dioxid e (2c) (2-m eth yl-7-p h en ylsa cch a r in ). A solution of 2b
(0.323 g, 1.00 mmol), phenyltributyltin (0.460 g, 1.25 mmol), and
Pd(Ph3P)2Cl2 (0.035 g, 0.050 mmol) in NMP (2.5 mL) was heated
at 120 °C under nitrogen in a sealed tube for 16 h. The mixture
was cooled, TBAF (1 M in THF, 2 mL) was added, and the
mixture was stirred at rt for 2 h. The mixture was diluted with
EtOAc, washed with water, dried, filtered, and evaporated. The
residue was fractionated over silica (EtOAc/hexane/CH2Cl2) to
give 2c (0.189 g, 69%): mp 154-156 °C; 1H NMR (CDCl3) δ 8.06
(1H, dd, J ) 1, 8), 7.85 (1H, apparent t, J ) 8), 7.79 (1H, dd, J
) 1, 8), 7.73-7.70 (2H, m), 7.56-7.52 (3H, m), 3.26 (3H, s); MS-
(CI) 291 M + NH4+. Anal. Calcd for C14H11NO3S: C, 61.52; H,
4.06; N, 5.12. Found: C, 61.42; H, 4.18; N, 5.08.
a
Me2NH, dioxane, rt, 85%; (b) n-BuLi, THF, -30 °C, I2, workup
and then rt 3 days, 68%; (c) n-BuLi, THF, -30 °C, Me2NCOCl; (d)
n-BuLi, THF, -50 °C, I2, rt 5 days, 47%; (e) KOH, DMSO, MeI,
89%; (f) Pd(Ph3P)2Cl2, DMF, Et3N, 55-60 °C, 5 h, 61% of 7; (g)
OsO4, NMO, dioxane/water, 86%; (h) NaIO4, dioxane/water, 94%.
7-endo cyclization has been reported in related systems.8,9
A two-step oxidation of the exo-methylene group of 7
completes the transformation (80% over the two steps)
to 1c, an 8-substituted oxicam derivative.
This sequence also proves the regiochemistry of iodi-
nation of 3a and, by analogy, of 3. If iodination of the
intermediate 2-(N,N-dimethylcarbamoyl)benzenesulfon-
amide 4b had occurred ortho to the carboxamide group,
the subsequent reactions would have given an isomer of
6 with the iodo substituent ortho to the ester group. This
compound could not have participated in the intramo-
lecular Heck reaction or furnished any of the products
7-9.
4-Hyd r oxy-8-iod o-3-(m eth oxyca r bon yl)-2-m eth yl-2H-1,2-
ben zoth ia zin e 1,1-Dioxid e 1b. To a solution of 2b (4.37 g,
13.5 mmol) and methyl chloroacetate (2.5 mL, 29 mmol) in
DMSO (20 mL) was added NaHMDS (1 M in THF, 28 mL)
dropwise over 10 min. The mixture was stirred at rt for 1.5 h
and then warmed at 60 °C for 1 h. Further methyl chloroacetate
(2.5 mL) and NaHMDS (14 mL) were added, and stirrring was
continued at 60 °C for 2 h. The mixture was diluted with EtOAc
and washed with water and 2% aqueous KOH. The organic
phase was dried filtered and evaporated to give recovered 2b
(2.33 g, 53%). The combined aqueous phase was acidified with
AcOH and extracted with EtOAc. This organic phase was
washed with 2% aqueous AcOH, dried, filtered, and evaporated.
Chromatography over silica gel gave 1b (1.90 g, 4.81 mmol,
We have described a straightforward and convenient
method for the synthesis of 7-substituted saccharins
using benzenesulfonamides or saccharins as starting
materials.10 These 7-substituted saccharins can be trans-
formed into 8-substituted oxicams by a standard ring
1
36%): mp 194-198 °C (EtOAc); H NMR (CDCl3) δ 11.92 (1H,
s), 8.23 (1H, dd, J ) 1, 8), 8.05 (1H, dd, J ) 1, 8), 7.33 (1H,
apparent t, J ) 8), 3.96 (3H, s), 3.02 (3H, s); MS(CI) 396 MH+.
Anal. Calcd for C11H10NO5SI: C, 33.43; H, 2.55; N, 3.54.
Found: C, 33.57; H, 2.53; N, 3.45.
2,7-Dim eth yl-1,2-ben zoisoth ia zol-3(2H)-on e 1,1-Dioxid e
(2a ) (2,7-dimethylsaccharin). To a solution of N-methylbenzene-
sulfonamide (4.63 g, 27.0 mmol) in THF (100 mL) cooled to -40
°C under argon was added n-BuLi (2 M in hexanes, 26 mL) at
(9) (a) Beckwith, A. L. J .; Meijs, G. F. J . Org. Chem. 1987, 52, 1922-
1930. (b) Brown, C. D. S.; Dishington, A. P.; Shishkin, O.; Simpkins,
N. Synlett. 1995, 943-944. (c) Gibson, S. E.; Middleton, R. J . J . Chem.
Soc., Chem. Commun. 1995, 1743-1744. (d) Ma, S.; Negishi, E.-I. J .
Am. Chem. Soc. 1995, 117, 6345-6357.
(10) While this work was in progress a conceptually similar di-ortho
functionalization of benzenesulfonate esters was reported. Spangler,
L. A. Tetrahedron Lett. 1996, 37, 3639-3642.

Notes
J . Org. Chem., Vol. 62, No. 6, 1997 1853
such a rate that the internal temperature remained below -30
°C. The mixture was stirred at -40 to -50 °C for 1 h.
Dimethylcarbamyl chloride (2.5 mL, 27 mmol) was added, and
the mixture was stirred at -30 °C for 20 min. The mixture was
cooled to -60 °C, n-BuLi (2 M in hexanes, 16 mL) was added,
and the mixture was stirred for 40 min. Iodomethane (2.0 mL,
27 mmol) was added all at once, and the mixture was stirred at
-50 °C for 30 min. The reaction was quenched by adding AcOH
(5 mL) and water (5 mL) and allowed to warm to rt. The mixture
was diluted with EtOAc and extracted with aqueous 2% NaOH.
The aqueous phase was acidified with HCl and extracted with
CHCl3. The organic phase was dried, filtered, evaporated, and
left at rt for 3 days to effect cyclization to the saccharin. The
crystalline product 2a was treated with a small amount of cold
methanol and collected by filtration (3.64 g, 62%): mp 97-99
°C; 1H NMR (CDCl3) δ 7.87 (1H, d, J ) 8), 7.68 (1H, apparent t,
J ) 8), 7.60 (1H, d, J ) 8), 3.26 (3H, s), 2.72 (3H, s); MS (CI)
229 M + NH4+. Anal. Calcd for C9H9NO3S: C, 51.17; H, 4.29;
N 6.63. Found: C, 51.08; H, 4.32; N, 6.66.
effect cyclization to the saccharin. Fractionation over silica gel
(CH2Cl2/hexane) gave 2e (3.06 g, 47%).
N-Allyl-N-m eth yl-2-iod o-6-(m eth oxyca r bon yl)ben zen e-
su lfon a m id e (6). To a solution of 2e (8.96 g, 25.7 mmol) in
DMSO (25 mL) stirred at rt was added crushed KOH (3.54 g,
63.1 mmol). The mixture was stirred at rt for 24 h, and
iodomethane (6.0 mL, 97 mmol) was added. After 5 h, the
mixture was diluted with EtOAc, washed with water, dried,
filtered, and evaporated. The residue was fractionated over
silica (hexane/CH2Cl2) to give 6 (8.64 g, 22.8 mmol, 89%) as an
oil that crystallized slowly on standing: mp 41-42 °C (iPr2O);
1H NMR (CDCl3) δ 8.18 (1H, dd, J ) 1, 8), 7.39 (1H, dd, J ) 1,
8), 7.19 (1H, apparent t, J ) 8), 5.79 (1H, m), 5.30-5.22 (2H,
m), 3.92 (3H, s), 3.92 (2H, d, J ) 6), 2.85 (3H, s). Anal. Calcd
for C12H14NO4SI: 36.47; H, 3.57, N, 3.54. Found: C, 36.49, H,
3.51, N, 3.38.
8-(Met h oxyca r b on yl)-4-m et h ylen e-3,4-d ih yd r o-2H -1,2-
ben zoth ia zin e 1,1-Dioxid e (7). A mixture of 6 (2.96 g, 7.82
mmol) and Pd(Ph3P)2Cl2 (0.125 g, 0.18 mmol) in Et3N (95 mL)
and DMF (10 mL) was degassed under vacuum and covered with
argon four times. The mixture was stirred under argon at 55-
60 °C for 5 h and then diluted with EtOAc, washed with water,
dried, filtered, and evaporated. Trituration of the crude product
4-Hydr oxy-3-(m eth oxycar bon yl)-2,8-dim eth yl-2H-1,2-ben -
zoth ia zin e 1,1-Dioxid e (1a ). To a solution of 2a (1.06 g, 5.0
mmol) and methyl chloroacetate (1.0 mL, 12 mmol) in DMSO
(10 mL) stirred at rt was added NaHMDS (1 M in THF, 10 mL)
dropwise with stirring. The mixture was then stirred at 60 °C
for 2.5 h. The mixture was diluted with EtOAc and extracted
with aqueous 0.5% KOH (2 × 50 mL). The aqueous phase was
acidified with acetic acid and extracted with CHCl3. The organic
phase was washed with water, dried, filtered, and evaporated.
Trituration of the residue with Et2O/CHCl3 gave 1a (0.50 g, 35%)
as a solid which was collected by filtration: mp 158-160 °C; 1H
NMR (CDCl3) δ 11.96 (1H, s), 7.90 (1H, d, J ) 8), 7.58 (1H,
apparent t, J ) 8), 7.48 (1H, d, J ) 8), 3.95 (3H, s), 2.99 (3H, s),
i
with Pr2O/CH2Cl2 gave crystalline 7 (1.13 g) which was collected
by filtration. Chromatography of the supernatant over silica gel
(eluent, CH2Cl2/hexane to CH2Cl2 gradient) gave a fraction from
which further product (0.15 g) crystallized (total yield, 1.28 g,
4.79 mmol, 61%): mp 150-152 °C (EtOAc/hexane); 1H NMR
(CDCl3) δ 7.89 (1H, dd, J ) 1, 8), 7.67 (1H, dd, J ) 1, 8), 7.57
(1H, apparent t, J ) 8), 5.97 (1H, s), 5.39 (1H, s), 4.49 (2H, s),
3.99 (3H, s), 2.71 (3H, s). Anal. Calcd for C12H13NO4S: C, 53.92;
H, 4.90; N, 5.24. Found: 53.59; H, 4.93; N, 5.19. The combined
residual supernatant from this and two other reactions was
fractionated by preparative layer chromatography to give
8-(m et h oxyca r b on yl)-4-m et h yl-2H-1,2-ben zot h ia zin e 1,1-
d ioxid e (8) as a foam: 1H NMR (CDCl3) δ 7.66-7.57 (3H), 6.40
(1H, br s), 4.01 (3H, s), 3.28 (3H, s), 2.20 (3H, d, J ) 1); MS (CI)
268 MH+. Anal. Calcd for C12H13NO4S: C, 53.92; H, 4.90; N,
5.24. Found: C, 53.71; H, 5.01; N, 5.17. Also obtained was
9-(m eth oxyca r bon yl)-2H-1,2-ben zoth ia zep in e 1,1-d ioxid e
(9): mp 82-84 °C (hexane); 1H NMR (CDCl3) δ 7.58-7.42 (3H),
6.51 (1H, dt, J )2, 13), 5.94 (1H, dt, J ) 3, 13), 4.22 (2H, br),
3.96 (3H, s), 2.67 (3H, s); MS (CI) 285 M + NH4+. Anal. Calcd
for C12H13NO4S: C, 53.92; H, 4.90; N, 5.24. Found: C, 53.80;
H, 4.83; N, 5.18.
2.72 (3H, s); MS (CI) 301 M + NH4+. Anal. Calcd for C12H13
-
NO5S: C, 50.88; H, 4.63; N, 4.94. Found: C, 50.90; H, 4.75; N,
4.73.
N -Ally l-2-(N ,N -d im e t h y lc a r b a m o y l)b e n ze n e s u lfo n -
a m id e (4a ). A mixture of 2d 7 (3.68 g, 16.5 mmol) and di-
methylamine (0.81 g) in dioxane (10 mL) was left at rt in a
stoppered flask for 31 h. The solvent was evaporated, and the
residue was taken up in EtOAc, washed with 0.5% aqueous HCl,
dried, filtered, and evaporated. The residue was fractionated
over silica gel to give 4a (3.86 g, 14.1 mmol, 85%) as an oil that
crystallized on standing: mp 47-49 °C; 1H NMR (CDCl3) δ 7.96
(1H, dd, J ) 1, 8), 7.57 (1H, apparent dt, J ) 1, 8), 7.52 (1H,
apparent dt, J ) 1, 7), 7.33 (1H, dd, J ) 1, 7) 5.77 - 5.62 (2H,
complex, CH + NH), 5.16 (1H, d, J ) 1, 7), 5.03 (1H, dd, J ) 1,
10) 3.66 (1H, br), 3.42 (1H, br), 3.12 (3H, s), 2.88 (3H, s). Anal.
Calcd for C12H16N2O3S: C, 53.71; H, 6.01; N, 10.44. Found: C,
53.97; H, 5.91; N, 10.49.
8-(Meth oxyca r bon yl)-4-h yd r oxy-4-(h yd r oxym eth yl)-3,4-
d ih yd r o-2H-1,2-ben zoth ia zin e 1,1-Dioxid e (10). A mixture
of 7 (1.28 g, 4.80 mmol), N-methylmorpholine N-oxide (0.605 g,
5.17 mmol), and OsO4 (4% aqueous solution, 0.1 mL) in dioxane
(25 mL) and water (10 mL) was stirred at rt for 40 h. The
mixture was diluted with EtOAc and washed with aqueous acetic
acid. The aqueous phase was back extracted with EtOAc, and
the combined organic phase was dried, filtered, and evaporated.
The residue was triturated with EtOAc/Et2O to give crystalline
10 (1.25 g, 4.15 mmol, 86%) collected by filtration: mp 161-
163 °C; 1H NMR (DMSO-d6) δ 7.88 (1H, dd, J ) 1, 8), 7.76 (1H,
apparent t, J ) 8), 7.65 (1H, dd, J ) 1, 8), 5.80 (1H, s, OH), 5.17
(1H, t, J ) 6, OH), 4.28 (1H, d, J ) 15), 3.82 (3H, s), 3.59-3.37
(3H, complex), 2.76 (3H, s); MS (CI) 302 MH+. Anal. Calcd for
C12H15NO6S: C, 47.83; H, 5.02; N, 4.65. Found: C, 48.25; H,
5.11; N, 4.40.
2-Allyl-7-iod o-1,2-ben zoisoth ia zol-3(2H)-on e 1,1-Dioxid e
(2e) (2-allyl-7-iodosaccharin). To a solution of 4a (0.514 g, 1.53
mmol) in THF (5 mL) cooled to -30 °C was added n-BuLi (2.5
M in hexanes 1.9 mL) dropwise over 10 min. After 5 min, iodine
(0.71 g, 2.8 mmol) in THF (3 mL) was added all at once, and the
mixture was allowed to warm to rt. The mixture was diluted
with EtOAc, washed with aqueous sodium thiosulfate, dried,
filtered, and evaporated. The residue was left standing at rt
for 3 days to effect cyclization to the saccharin. Chromatography
over silica (EtOAc/hexane) gave 2e (0.369 g, 1.05 mmol, 68%)
as an oil that crystallized on standing: mp 82-83 °C (EtOAc/
hexane); 1H NMR (CDCl3) δ 8.18 (1H, dd, J ) 1, 8), 8.03 (1H,
dd, J ) 1, 8), 7.49 (1H, apparent t, J ) 8), 5.96 (1H, m), 5.46
(1H, dd, J ) 1, 7), 5.33 (1H, dd, J ) 1, 10), 4.40 (2H, d, J ) 6).
Anal. Calcd for C10H8NO3SI: C, 34.40; H, 2.31; N, 4.01.
Found: C, 34.68; H, 2.23; N, 3.94.
3,4-Dih ydr o-8-(m eth oxycar bon yl)-4-oxo-2H-1,2-ben zoth i-
a zin e 1,1-Dioxid e (1c). To a solution of 10 (0.300 g, 0.99 mmol)
in dioxane (10 mL, warmed to dissolve) was added water (10
mL) followed by NaIO4 (0.225 g, 1.06 mmol) in water (5 mL).
The mixture was stirred at rt for 20 min, when TLC showed
complete conversion. The mixture was diluted with EtOAc,
washed with water, dried, filtered, and evaporated to give 1c
2-Allyl-7-iod osa cch a r in 2e is also obtained from N-allyl-
benzenesulfonamide 3a as follows. To a solution of 3a (3.61 g,
18.2 mmol) in THF (30 mL) cooled below -30 °C under argon
was added n-BuLi (2 M in cyclohexane, 21 mL, 42 mmol).
Dimethylcarbamyl chloride (2.2 mL, 24 mmol) was added all at
once. The mixture was stirred for 10 min and, after cooling to
-50 °C, further n-BuLi (2 M in cyclohexane, 10 mL) was added.
The mixture was stirred for 30 min, iodine (4.94 g, 19.2 mmol)
in THF (15 mL) was added rapidly, and the mixture was allowed
to warm to rt. The mixture was diluted with EtOAc, washed
with aqueous sodium thiosulfate and water, dried, filtered, and
evaporated. The residue was left standing at rt for 5 days to
1
(0.253g, 0.94 mmol, 94%): mp 148-150 °C; H NMR (CDCl3) δ
8.22 (1H, dd, J ) 1, 8), 8.03 (1H, dd, J ) 1, 8), 7.79 (1H, apparent
t, J ) 8), 4.45 (2H, s), 4.02 (3H, s), 2.90 (3H, s); MS (CI) 287 M
+
+ NH4
. Anal. Calcd for C11H11NO5S: C, 49.06; H, 4.11; N,
5.20. Found: C, 48.88; H, 4.07; N, 5.09.
J O961955W